title: Autophagy induced by HIF1α overexpression supports trophoblast invasion by supplying cellular energy.
abstract: Extravillous trophoblasts (EVTs) characterize the invasion of the maternal decidua under low oxygen and poor nutrition at the early feto-maternal interface to establish a successful pregnancy. We previously reported that autophagy in EVTs was activated under 2% O2 in vitro, and autophagy activation was also observed in EVTs at the early feto-maternal interface in vivo. Here, we show that autophagy is an energy source for the invasion of EVTs. Cobalt chloride (CoCl2), which induces hypoxia inducible factor 1α (HIF1α) overexpression, activated autophagy in HTR8/SVneo cells, an EVT cell line. The number of invading HTR8-ATG4B(C74A) cells, an autophagy-deficient EVT cell line, was markedly reduced by 81 percent with the CoCl2 treatment through the suppression of MMP9 level, although CoCl2 did not affect the cellular invasion of HTR8-mStrawberry cells, a control cell line. HTR8-ATG4B(C74A) cells treated with CoCl2 showed a decrease in cellular adenosine triphosphate (ATP) levels and a compensatory increase in the expression of purinergic receptor P2X ligand-gated ion channel 7 (P2RX7), which is stimulated with ATP, whereas HTR8-mStrawberry cells maintained cellular ATP levels and did not affect P2RX7 expression. Furthermore, the decreased invasiveness of HTR8-ATG4B(C74A) cells treated with CoCl2 was neutralized by ATP supplementation to the level of HTR8-ATG4B(C74A) cells treated without CoCl2. These results suggest that autophagy plays a role in maintaining homeostasis by countervailing HIF1α-mediated cellular energy consumption in EVTs.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toyama, Toyama, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Yamanaka-Tatematsu
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Nakashima
authors.forename: Naonobu
authors.initials: N
authors.lastname: Fujita
authors.forename: Tomoko
authors.initials: T
authors.lastname: Shima
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshimori
authors.forename: Shigeru
authors.initials: S
authors.lastname: Saito
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics*; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D003035:Cobalt / Q000494:pharmacology; D003656:Decidua / Q000166:cytology / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C546468:P2RX7 protein, human; D058486:Receptors, Purinergic P2X7; D003035:Cobalt; D000255:Adenosine Triphosphate; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C018021:cobaltous chloride